Ribosome 18S m6A Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth
Ribosome 18S m6A Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth
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核糖体 18S m6A 甲基转移酶 METTL5 促进翻译起始和乳腺癌细胞生长
DOI：
10.1016/j.celrep.2020.108544
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发表时间：
2020-12-22
期刊：
影响因子：
8.8
通讯作者：
Lan, Fei
中科院分区：
文献类型：
--
作者：
Rong, Bowen;Zhang, Qian;Lan, Fei
哺乳动物18 S rRNA的腺苷1832（m（6）A1832）处的N6甲基化，占据解码中心内的关键位置，被保守的甲基转移酶，胃L5修饰。在此，我们发现胃L5对18 S A1832基序表现出强烈的底物偏好性，而不是其他报道的m（6）A基序。与在该位点未修饰的酵母核糖体结构模型的比较表明，该修饰可以通过诱导哺乳动物核糖体解码中心的构象变化来促进mRNA结合。胃L5促进p70-S6 K活化和适当的翻译起始，并且胃L5的丢失显著降低了多核糖体的丰度。在乳腺癌患者样品中，胃L5表达升高，并且是几种乳腺癌细胞系生长所需的。我们进一步发现，秀丽隐杆线虫缺乏同源物metl-5开发表型已知与受损的翻译。总之，我们的发现揭示了胃L5在翻译调控中的关键和保守作用。
N6 methylation at adenosine 1832 (m(6)A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m(6)A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.